Differential expression of cyclic nucleotide phosphodiesterases 4 in developing rat lung

López, E.; Jarreau, Pierre‐Henri; Zana, Elodie; Franco-Montoya, Marie-Laure; Schmitz, Thomas; Évain-Brion, Danièle; Bourbon, Jacques R.; Delacourt, Christophe; Méhats, Céline

doi:10.1002/dvdy.22374

Cited by 5 publications

(6 citation statements)

References 27 publications

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“…As expected, these isoenzyme proteins were abundantly found in the cytosolic fraction, which is likely correlated with the presence of high cAMP hydrolytic activity. PDE4A (64 and 84 kDa) was only found in the cytosolic fraction, whereas 64 kDa PDE4B and 63 kDa PDE4D were differentially expressed in this compartment (16). As for the microsomal fraction, 51 kDa PDE4A and mainly three PDE4C immunoreactive bands (84, 75, and 64 kDa) were the predominant forms, with 75 kDa PDE4C being exclusively expressed in this fraction.…”

Section: Discussionmentioning

confidence: 97%

mentioning

confidence: 99%

“…Consequently, PDE4 is thought to play a key role in lung inflammation and hyperresponsiveness. Despite increasing evidence, which depict PDE4 family enzymes as attractive targets for treatment of asthma and COPD (6, 22), little is known regarding their relative activities and expression in human lung tissue (16,36,41).The main objectives of this study were as follows: 1) to characterize subcellular cAMP-PDE activities and PDE4 isoform expression in human lung parenchyma and 2) to assess whether NCS 613, a specific PDE4 inhibitor (1, 2), is able to modulate inflammation in human lung parenchyma and hyperresponsiveness triggered in distal bronchi. Herein, we report cAMP-PDE activities and for the first time the subcellular expression of PDE4 isozymes in human lung parenchyma, as well as anti-inflammatory effects of NCS 613 on this tissue.…”

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confidence: 99%

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NCS 613, a potent and specific PDE4 inhibitor, displays anti-inflammatory effects on human lung tissues

Yougbaré

Morin²,

Senouvo³

et al. 2011

American Journal of Physiology-Lung Cellular and Molecular Phys

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Chronic inflammation is a hallmark of pulmonary diseases, which leads to lung parenchyma destruction (emphysema) and obstructive bronchiolitis occurring in both chronic obstructive pulmonary disease and asthma. Inflammation is strongly correlated with low intracellular cAMP levels and increase in specific cAMP hydrolyzing activity. The aim of the present study was to investigate the role of the cyclic phosphodiesterase type 4 (PDE4) in human lung and to determine the effects of NCS 613, a new PDE4 inhibitor, on lung inflammation and bronchial hyperresponsiveness. High cAMP-PDE activities were found in the cytosoluble fractions from human lung parenchyma and distal bronchi. PDE4 (rolipram sensitive) represented 40% and 56% of total cAMP-PDE activities in the above-corresponding tissues. Moreover, PDE4A, PDE4B, PDE4C, and PDE4D isoforms were detected in all three subcellular fractions (cytosolic, microsomal, and nuclear) with differential distributions according to specific variants. Pharmacological treatments with NCS 613 significantly decreased PDE4 activity and reduced IκBα degradation in cultured parenchyma, both of which are usually correlated with a lower inflammation status. Moreover, NCS 613 pretreatment potentiated isoproterenol-induced relaxations in human distal bronchi, while reducing TNF-α-induced hyperresponsiveness in cultured bronchi, as assessed in the presence of methacholine, U-46619, or histamine. This reducing effect of NCS 613 on human bronchi hyperresponsiveness triggered by TNF-α was related to a lower expression level of PDE4B and PDE4C, as well as a downregulation of the phosphorylated forms of p38-MAPK, CPI-17, and MYPT-1, which are known to control tone. In conclusion, specific PDE4 inhibitors, such as NCS 613, may represent an alternative and isoform-specific approach toward reducing human lung inflammation and airway overreactivity.

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Section: Discussionmentioning

confidence: 97%

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confidence: 99%

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confidence: 99%

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NCS 613, a potent and specific PDE4 inhibitor, displays anti-inflammatory effects on human lung tissues

Yougbaré

Morin²,

Senouvo³

et al. 2011

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Different PDE isoforms are expressed in different epithelial cells. Whereas whole lung tissue primarily expresses PDE4 [ 187 ], primary alveolar A549 cells highly express PDE4 compared to PDE1, PDE3 and PDE5 and primary human bronchial epithelial (HBE) cells equally express PDE4 and PDE1, but express lower levels of PDE3 and PDE5 [ 131 , 132 ]. In contrast to studies in endothelial cells, cAMP-sensing multiprotein complexes maintained by AKAPs have not been studied yet in airway epithelial cells, even though PDE4 is complexed with AKAP9 [ 123 ].…”

Section: Spatio-temporal Nature Of Compartmentalized Camp Signallimentioning

confidence: 99%

Multiple Facets of cAMP Signalling and Physiological Impact: cAMP Compartmentalization in the Lung

2012

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Therapies involving elevation of the endogenous suppressor cyclic AMP (cAMP) are currently used in the treatment of several chronic inflammatory disorders, including chronic obstructive pulmonary disease (COPD). Characteristics of COPD are airway obstruction, airway inflammation and airway remodelling, processes encompassed by increased airway smooth muscle mass, epithelial changes, goblet cell and submucosal gland hyperplasia. In addition to inflammatory cells, airway smooth muscle cells and (myo)fibroblasts, epithelial cells underpin a variety of key responses in the airways such as inflammatory cytokine release, airway remodelling, mucus hypersecretion and airway barrier function. Cigarette smoke, being next to environmental pollution the main cause of COPD, is believed to cause epithelial hyperpermeability by disrupting the barrier function. Here we will focus on the most recent progress on compartmentalized signalling by cAMP. In addition to G protein-coupled receptors, adenylyl cyclases, cAMP-specific phospho-diesterases (PDEs) maintain compartmentalized cAMP signalling. Intriguingly, spatially discrete cAMP-sensing signalling complexes seem also to involve distinct members of the A-kinase anchoring (AKAP) superfamily and IQ motif containing GTPase activating protein (IQGAPs). In this review, we will highlight the interaction between cAMP and the epithelial barrier to retain proper lung function and to alleviate COPD symptoms and focus on the possible molecular mechanisms involved in this process. Future studies should include the development of cAMP-sensing multiprotein complex specific disruptors and/or stabilizers to orchestrate cellular functions. Compartmentalized cAMP signalling regulates important cellular processes in the lung and may serve as a therapeutic target.

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“…Abundance of PDE 4 in lung tissue has been reported earlier 26 . PDE-4 has four distinct genes, PDE-4A, PDE-4B, PDE-4C and PDE-4D 27 with specificity to cAMP and thus have become potential therapeutic targets.…”

Section: Discussionmentioning

confidence: 72%

A novel triazine-aryl-bis-indole derivative inhibits both phosphodiesterase IV and expression of cell adhesion molecules

et al. 2015

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Differential expression of cyclic nucleotide phosphodiesterases 4 in developing rat lung

Cited by 5 publications

References 27 publications

NCS 613, a potent and specific PDE4 inhibitor, displays anti-inflammatory effects on human lung tissues

NCS 613, a potent and specific PDE4 inhibitor, displays anti-inflammatory effects on human lung tissues

Multiple Facets of cAMP Signalling and Physiological Impact: cAMP Compartmentalization in the Lung

A novel triazine-aryl-bis-indole derivative inhibits both phosphodiesterase IV and expression of cell adhesion molecules

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